The overall goal for this research is to understand in greater detail and to investigate the "volume effect" in radiotherapy. The rationale for these studies is based on the observation in clinical radiotherapy that for a given tissue the total dose that can be "tolerated" depends on the volume of tissue irradiated. An unresolved issue in radiotherapy is if, how, and why an increase in volume decreases the total dose for a given level of normal tissue reaction as opposed to its symptomatic tolerability. The hypothesis underlying this proposal is that the relation of the probability of normal tissue damage to the volume irradiated is based primarily on the presence (or absence) and secondarily on the organization of functional subunits (FSU) within the tissues. The three tissues chosen for study are the lung, bowel mucosa, and bowel wall in mice which we suggest represent a parallel arrangement of FSUs (lung), a linear arrangement with cell migration moderating the radiation damage (bowel mucosa), and a tissue without FSUs (bowel wall). We suggest that all three tissues will exhibit a volume effect but that functional impairment in lung and bowel mucosa will occur only when a threshold volume is exceeded and that the effect of a threshold volume in these tissues will be to steepen the volume response curve. Conversely, in the bowel wall we predict no threshold volume. The experimental approach will be to irradiate varying volumes of the lung or the colorectal area in mice with graded doses to assess the volume and dose dependence for functional impairment. Assays of morbidity will be increases in breathing rate and deaths from pneumonitis for the lung and the incidence of either consequential or primary obstructions for the colon. The potential importance of these studies to radiotherapy is that these data may provide a rational basis for changing total doses as volume changes in dose limiting normal tissues.